EP2146209A1 - Marqueurs neuro-dégénératifs pour la maladie d'Alzheimer - Google Patents

Marqueurs neuro-dégénératifs pour la maladie d'Alzheimer Download PDF

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EP2146209A1
EP2146209A1 EP09013088A EP09013088A EP2146209A1 EP 2146209 A1 EP2146209 A1 EP 2146209A1 EP 09013088 A EP09013088 A EP 09013088A EP 09013088 A EP09013088 A EP 09013088A EP 2146209 A1 EP2146209 A1 EP 2146209A1
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Prior art keywords
concentration
value
disease
normal
tryptophan
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EP2146209B1 (fr
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Aye Mu Myint
Manfred Schawaller
Markus J. Schwarz
Harald Hampel
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Universiteit Antwerpen
Klinik und Poliklinik fur Psychiatrie und Psychotherapie
Universiteit Maastricht
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Universiteit Antwerpen
Klinik und Poliklinik fur Psychiatrie und Psychotherapie
Universiteit Maastricht
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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6893—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to diseases not provided for elsewhere
    • G01N33/6896—Neurological disorders, e.g. Alzheimer's disease
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/94—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving narcotics or drugs or pharmaceuticals, neurotransmitters or associated receptors
    • G01N33/9406—Neurotransmitters
    • G01N33/942—Serotonin, i.e. 5-hydroxy-tryptamine
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/28—Neurological disorders
    • G01N2800/2814—Dementia; Cognitive disorders
    • G01N2800/2821—Alzheimer
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
    • Y10T436/00—Chemistry: analytical and immunological testing
    • Y10T436/14—Heterocyclic carbon compound [i.e., O, S, N, Se, Te, as only ring hetero atom]
    • Y10T436/145555—Hetero-N

Definitions

  • the present invention relates to methods for detecting a psychiatric condition optionally associated with a depression comprising the steps of measuring the concentration of at least one in vivo degradation product of tryptophan. Further, the present invention relates to the use of said values as predictive markers for the detection of a psychiatric condition optionally associated with a depression and a kit containing means for detecting said values.
  • Depression is a major psychiatric disorder with an overall incidence of 12.3% with 14.1% for female and 8.6% for male in Europe ( Copeland JR, Beekman AT, Dewey ME, Hooijer C, 1999, Depression in Europe. Geographical distribution among older people. Br. J. Psychiatry; 174:312-321 ).
  • National Mental Health Association American employees took around three million days off work every year due to untreated depression and that is more than employees used for other physical illnesses like diabetes, high blood pressure and arthritis ( Burns H, Charleston Regional Business Journal, April, 2004 ).
  • AD Alzheimer's disease
  • pseudodementia or dementia syndrome of depression a progressive neurodegenerative disorder of the human brain.
  • AD Tekin,S. and Cummings,J.L. (2001). Depression in dementia. Neurologist 7, 252-259 ).
  • the prevalence of depression ranges between 15 and 50% in patients with AD ( Rovner,B.W., Broadhead,J., Spencer,M., Carson,K., and Folstein,M.F. (1989). Depression and Alzheimer's disease. Am. J.
  • Psychiatry 146 350-353 .; Migliorelli,R., Teson,A., Sabe,L., Petracchi,M., Leiguarda,R., and Starkstein,S.E. (1995). Prevalence and correlates of dysthymia and major depression among patients with Alzheimer's disease. Am. J. Psychiatry 152, 37-44 ) and several authors suggested that depressive symptoms are part of the preclinical phase of AD ( Berger,A.K., Fratiglioni,L., Forsell,Y., Winblad,B., and Backman,L. (1999). The occurrence of depressive symptoms in the preclinical phase of AD: a population-based study.
  • Serotonin is a neurochemical which is necessary for the brain for the good mood and growth factors for the brain, and which is synthesized from tryptophan.
  • Tryptophan is an amino acid from the food and from the body amino acid pool. Tryptophan is partly broken down by an enzyme, indoleamine 2,3-dioxygenase, which is present in the lungs, white blood cells, placenta and the brain ( Heyes MP, Satio K, Markey SP, 1992, Human macrophages convert L-tryptophan into the neurotoxin quinolinic acid. Biochem. J.; 283(3):633-635 ; Mellor AL and Munn DH, 1999, Tryptophan catabolism and T-cell tolerance: immunosuppression by starvation.
  • kynurenine which is the first metabolite of tryptophan ( Bender DA, 1989, The kynurenine pathway of tryptophan metabolism: In TW Stone (ed). Quinolinic acid and kynurenines. Boca Raton FL: CRC Press: 3-38 ).
  • This kynurenine is again broken down into two pathways: (1) neuroprotective, kynurenic acid and (2) neurodegenerative 3-hydroxykynurenine (3-HK), hydroxyanthranilic acid and quinolinic acid ( Chiarugi A, Calvani M, Meli E, Traggiai E, Moroni F, 2001, Synthesis and release of neurotoxic kynurenine metabolites by human monocyte derived macrophages. J Neuroimmuno1;120(1-2):190-198 ).
  • the problem underlying the present invention is to provide a new method for detecting a psychiatric condition using low molecular weight biochemical markers.
  • the present invention relates to a method for detecting a psychiatric condition optionally associated with a depression comprising the step of measuring the concentration of at least one in vivo degradation product of tryptophan, preferably 3-hydroxykynurenine, quinolinic acid, melatonin, serotonin, 5-hydroxyindoleacetic acid, kynurenic acid and/or kynurenine, in a blood plasma sample obtained from the individuum being examined, and assessing the psychiatric condition.
  • tryptophan preferably 3-hydroxykynurenine, quinolinic acid, melatonin, serotonin, 5-hydroxyindoleacetic acid, kynurenic acid and/or kynurenine
  • the term "degradation product of tryptophan” as used herein also includes tryptophan.
  • the blood plasma sample can be obtained by any method known in the art. In a preferred embodiment of the present invention an overnight-fasting early morning blood sample of a patient is collected in a heparinised tube. The blood plasma is obtained via centrifugation of said heparinised tube which results in a separation of the plasma fraction which forms the supernatant. In a more preferred embodiment the plasma is frozen, most preferably at -70°C, before measuring the concentration of at least one in vivo degradation product of tryptophan.
  • body fluids such as whole blood, serum, urine, saliva and cerebrospinal fluid (CSF) can also be used in the present invention. These body fluids can be obtained by methods known in the art.
  • the above method further comprises the step of measuring the concentration of kynurenine in the blood plasma sample.
  • the above method further comprises the step of measuring the concentration of 3-hydroxykynurenine in the blood plasma sample.
  • the measurement of the concentration of tryptophan and/or degradation products such as 3-hydroxykynurenine and/or kynurenic acid and/or kynurenine in a body fluid such as a blood plasma sample can be carried out by any method known in the art.
  • the measurement of the concentration of the analytes, especially the degradation products of tryptophan is carried out using High Performance Liquid Chromatography, in a more preferred embodiment using a UV detector and/or a flourescent detector, and/or an immunoassay and/or a ligand binding assay.
  • the analytes are determined by a ligand binding assay, for example an immunoassay based on antibodies or a receptor binding assay or an enzyme binding assay or competitive versions of one or more of those assays.
  • the samples are for example substantially deproteinated (all proteins are removed) before measuring the concentration of at least one in vivo degradation product of tryptophan, preferably 3-hydroxykynurenine, kynurenic acid, and/or kynurenine.
  • the neuroprotective ratio may be determined by dividing the value of the concentration of kynurenic acid by the value of the concentration of kynurenine in said blood plasma sample (kynurenic acid value/kynurenine value).
  • an individuum having a psychiatric condition optionally associated with a depression is characterized by a neuroprotective ratio in the blood plasma of about 0 to about 18, more preferably about 3 to about 17, and most preferably about 6 to about 16.3.
  • the neuroprotective index may be determined by dividing the square value of the concentration of kynurenic acid by the value of the concentration of kynurenine in said blood plasma sample (kynurenic acid value 2 /kynurenine value).
  • an individuum having a psychiatric condition optionally associated with a depression is characterized by a neuroprotective index in the blood plasma of about 0 to about 700, more preferably about 100 to about 600, and most preferably about 200 to about 473.
  • the ratio (“neurodegenerative ratio”) may be determined by dividing the value of the concentration of 3-hydroxykynurenine by the value of the concentration of kynurenic acid or of tryptophan (3-hydroxykynurenine value/kynurenic acid value or 3-hydroxykynurenine value/ tryptophan value).
  • the ratio determined by dividing the value of the concentration of 3-hydroxykynurenine by the value of the concentration of kynurenic acid is significantly increased when compared to healthy individuals and preferably the psychiatric condition optionally associated with a depression is Alzheimer's disease (AD).
  • AD Alzheimer's disease
  • an individuum having a psychiatric condition optionally associated with a depression is characterized by a ratio determined by dividing the value of the concentration of 3-hydroxykynurenine by the value of the concentration of kynurenic acid or of tryptophan in the blood plasma. For example, if the ratio is about two or higher, provided that the analytes are given in the same unit, this is considered as an indication of Alzheimer's disease. The same applies to the ratio determined by dividing the value of the concentration of 3-hydroxykynurenine multiplied by the factor 1000 by the value of the concentration of tryptophan in the blood plasma; i.e. 3-HK is multiplied by the factor 1000, provided that the analytes are given in the same unit (3-HK x 1000 / TRP).
  • the present invention further relates to a method for detecting a psychiatric condition optionally associated with a depression comprising the step of combining at least two values selected from the group consisting of the concentration of kynurenic acid, the neuroprotective ratio, the ratio determined by dividing the value of the concentration of 3-hydroxykynurenine by the value of the concentration of kynurenic acid, the ratio determined by dividing the value of the concentration of 3-hydroxykynurenine by the value of the concentration of tryptophan and the neuroprotective index of a blood plasma sample in order to improve the specificity and/or sensitivity of the detection of said psychiatric condition.
  • Methods for detecting a psychiatric condition optionally associated with a depression comprising the measurement of at least one other neurodegenerative, neuroprotective, or neurotrophic marker(s) in combination with the measurement of the concentration of at least one in vivo degradation product of tryptophan are also part of the present invention.
  • the present invention relates to (i) the use of kynurenic acid as a predictive marker for the detection of a psychiatric condition optionally associated with a depression, and/or (ii) the use of a neuroprotective ratio determined by dividing the value of the concentration of kynurenic acid by the value of the concentration of kynurenine in a blood plasma sample as a predictive marker for the detection of a psychiatric condition optionally associated with a depression, and/or (iii) the use of a ratio determined by dividing the value of the concentration of 3-hydroxykynurenine by the value of the concentration of kynurenic acid for the detection of a psychiatric condition optionally associated with a depression, and/or
  • the present invention also relates to the use of a combination of at least two values selected from the group consisting of the concentration of kynurenic acid, the neuroprotective ratio, the ratio determined by dividing the value of the concentration of 3-hydroxykynurenine by the value of the concentration of kynurenic acid, the ratio determined by dividing the value of the concentration of 3-hydroxykynurenine by the value of the concentration of tryptophan, and the neuroprotective index of a blood plasma as predictive markers for the detection of a psychiatric condition optionally associated with a depression.
  • the present invention also relates to the use of a combination of the concentration of kynurenic acid, the neuroprotective ratio, the ratio determined by dividing the value of the concentration of 3-hydroxykynurenine by the value of the concentration of kynurenic acid, the neuroprotective index of a blood plasma, the ratio determined by dividing the value of the concentration of 3-hydroxykynurenine by the value of the concentration of tryptophan, and/or at least one other neuroprotective, neurodegenerative or neurotrophic marker(s) as predictive markers for the detection of a psychiatric condition optionally associated with a depression.
  • predictive marker or “biological marker” as used herein means that the factor used as a biological or predictive marker, preferably the concentration of kynurenic acid in blood plasma, the neuroprotective ratio, the ratio determined by dividing the value of the concentration of 3-hydroxykynurenine by the value of the concentration of kynurenic acid, the neuroprotective index, the ratio determined by dividing the value of the concentration of 3-hydroxykynurenine by the value of the concentration of tryptophan, or a combination thereof, is indicative regarding the question whether an individuum has a psychiatric condition optionally associated with a depression or not.
  • the present invention also relates to a kit for detecting a psychiatric condition containing means for detecting the concentration of a tryptophan degeneration product in a body fluid such as whole blood, serum, plasma, urine, saliva and CSF can also be used in the present invention.
  • a body fluid such as whole blood, serum, plasma, urine, saliva and CSF
  • the kit contains means for detecting the concentration of kynurenic acid and/or kynurenine and/or 3-hydroxykynurenine and/or tryptophan in said blood plasma sample.
  • the present invention also relates to therapeutic interventions that change any of the above mentioned biomarkers.
  • Figure 1 shows the frequency of the kynurenic acid concentrations in nanomole/litre as obtained in Example 1.
  • Figure 2 shows the frequency of the neuroprotective ratio (KAKYN) as obtained in Example 1.
  • FIG. 3 shows the frequency of the neuroprotective index (PROi) as obtained in Example 1.
  • FIG. 4 shows the Receiver Operating Characteristic (ROC) curve for kynurenic acid (KA) as obtained in Example 1.
  • Figure 5 shows the ROC curve for the neuroprotective ratio (KAKYN) as obtained in Example 1.
  • Figure 6 shows the ROC curve for the neuroprotective index (PROi) as obtained in Example 1.
  • Figure 7 shows ratios between serum levels of 3-HK and TRP in patients with Alzheimer's disease (AD), patients with major depression (MD), and healthy persons with subjective cognitive impairment (SCI).
  • AD Alzheimer's disease
  • MD major depression
  • SCI subjective cognitive impairment
  • AD Patients with Alzheimer's disease
  • MD Patients with major depression
  • SCI Healthy persons with subjective cognitive impairment
  • MMSE Mini-Mental State Examination.
  • Table 3 shows mobile phases and gradient conditions.
  • Solvent A 50 mM sodium acetate, pH 4.8; solvent B: 50 mM sodium acetate, pH 3.56; solvent C: 100% acetonitrile; solvent D: 100% methanol.
  • Table 4 shows serum levels of tryptophan (TRP), kynurenine (KYN), kynurenic acid (KYNA), and 3-hydroxykynurenine (3-HK) in patients with Alzheimer's disease (AD), patients with major depression (MD), and healthy persons with subjective cognitive impairment (SCI).
  • TRP tryptophan
  • KYN kynurenine
  • KYNA kynurenic acid
  • SCI healthy persons with subjective cognitive impairment
  • Example 1 Measurement of neuroprotective index, neuroprotective ratio and plasma kynurenine concentrations in human blood plasma
  • a total of 10 ml of overnight-fasting early morning blood samples were collected in heparinised tubes and plasma samples were collected and stored at -70°C for analyses at a later date. For the patients, another samplings were done at the time of discharge.
  • the tryptophan index (TRPi) which represents the tryptophan availability in the blood (100 x tryptophan value/sum of competing amino acids values), tryptophan breakdown index (KYN/TRP) which represents the tryptophan breakdown (kynurenine value/tryptophan value), and neuroprotective ratio (KAKYN) (kynurenic acid value/kynurenine value) and neuroprotective index (PROi) (kynurenic acid value 2 /kynurenine value) which represent the strength of neuroprotection against quinolinic excitotoxic effect were calculated (Table 1).
  • the neuroprotective index, neuroprotective ratio and plasma kynurenic acid concentrations are biological markers to be used to differentiate between normal and depressed persons.
  • Example 2 Determination of kynurenine and kynurenic acid using High Performance Liquid Chromatography
  • Example 5 Determination of Elevated 3-Hydroxykynurenine serum levels in Alzheimer's Disease
  • AD Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition Text Revision. (Washington, DC: American Psychiatric Associati on)). Mean duration of illness in the AD group is 2.20 years (0-5 years). All AD patients are free of antidementive treatment, and have no actual treatment with NSAIDs (Non-Steroidal Anti-Imflammatory Drugs). One of the AD patients had a previous history of remitting-relapsing major depression, but is admitted to the hospital without any depressive symptoms and free of anti-depressive medication.
  • NSAIDs Non-Steroidal Anti-Imflammatory Drugs
  • Serum samples are collected in vacucontainers without further additives. After 0.5 hours of coagulation, samples are centrifuged and the supernatant is aliquoted into Eppendorf cups (Eppendorf, Hamburg, Germany) and immediately frozen at -80°C.
  • HPLC high-performance liquid chromatographic
  • PBS Phosphate buffered saline
  • Tryptophan, kynurenine, kynurenic acid, and 3-hydroxykynurenine are purchased in high purity from Sigma (St. Louis, MO).
  • Calibrators and controls are established by adding defined concentrations of the analytes to a 0.05 M PBS solution.
  • concentrations are used for five-point calibration: TRP: 0.313, 0.625, 1.25, 2.5, 5.0, 10.0, 20.0 ⁇ g/ml; KYN: 12.5, 25.0, 50.0, 100, 200, 400, 800 ng/ml; KYNA: 4.688, 9.375, 18.75, 37.5, 75.0, 150, 300 ng/ml; 3-HK: 1.563, 3.125, 6.25, 12.5, 25.0, 50.0, 100 ng/ml.
  • Analytes are extracted from samples and calibrators/controls using Waters Oasis MCX 1 cc (30 mg) extraction cartridges (Waters, Milford, MS) as follows (all extractions are conducted with a manual vacuum-manifold system): (1) the cartridge is preconditioned by rinsing with 1 ml of methanol followed by 1 ml water; (2) 1 ml sample and 100 ⁇ l 1 M H 3 PO 4 are applied to the cartridge and pulled through under a light vacuum (2 minutes); (3) the cartridge is washed with 1 ml of 0.1 M HCl followed by 1 ml 100% methanol; and finally, (4) the analytes are eluted by rinsing the cartridge with 1.5 ml of acetonitrile containing 6% NaOH.
  • the eluent is then evaporated under nitrogen to dryness and reconstituted with 150 ⁇ l 0.1 M PBS.
  • the reconstituted sample/calibrator/control is then transferred to a microinjection vial (Waters).
  • HPLC Equipment and chromatographic conditions Analyses are carried out on a Waters 2695 chromatograph connected to a Waters Model 2487 dual- ⁇ UV detector and a 2475 fluorescence detector.
  • elution is carried out in the gradient mode using a mobile phase consisting of a mixture of 0.050 M sodium acetate (solvent A: pH 4.80; solvent B: pH 3.65), acetonitrile (solvent C), and methanol (solvent D) at distinct proportions (see Table 3).
  • Flow rate is set at 0.80 ml/minute, column temperature is set at 35.0 °C, while the samples are cooled at 4.0°C.
  • TRP is measured by fluorescence detection ( ⁇ ex: 300 nm; ⁇ em: 350 nm), KYN (365 nm), KYNA (330 nm), and 3-HK (365 nm) are measured by UV detection. Approximate run time after injection until detection of the compounds is about 20.4 minutes for TRP, 13.4 minutes for KYN, 22.5 minutes for KYNA, and 7.0 minutes for 3-HK.
  • SPSS version 12.0.1; SPSS, Chicago, Illinois
  • nonparametric procedures Kruskal-Wallis-Test - Mann-Whitney-Test - Spearman-Rank correlation
  • Level of significance is set at p ⁇ 0.050.
  • a linear model with diagnosis as independent factor and age as covariate is used.
  • the outcome variables are not normally distributed by visual inspection of the regression residuals and Kolmogorov Smirnov tests (p ⁇ 0.05)
  • bootstrapping applied to a multiple regression model with diagnosis and age as independent predictor variables for a distribution free significance test is used.
  • the multiple regression model for each pair of diagnoses on the basis of 999 samples is iteratively computed.
  • sensitivity of the marker when specificity is set at > 80% and specificity when sensitivity is set at > 80% using ROC analysis is determined.
  • the level of 80% is chosen based on the consensus criteria for a clinically useful biomarker in AD (The Ronald and Nancy Reagan Research Institute of the Alzheimer's Association and the National Institute on Aging Working Group (1998). Consensus report of the Working Group on: " Molecular and Biochemical Markers of Alzheimer's Disease". The Ronald and Nancy Reagan Research Institute of the Alzheimer's Association and the National Institute on Aging Working Group. Neurobiol. Aging 19, 109-116 .).
  • TRP tryptophan
  • KYN kynurenine
  • KYNA kynurenic acid
  • SCI 3-hydroxykynurenine
  • 3-HK levels are significantly different between AD patients and SCI controls (partial correlation coefficient -0.42, p ⁇ 0.05) and between AD and MD patients (partial correlation coefficient -0.35, p ⁇ 0.05).
  • the ratio of 3-HK to TRP is significantly different between AD patients and SCI controls (partial correlation coefficient -0.47, p ⁇ 0.05), but not between AD and MD patients (partial correlation coefficient -0.2).
  • 3-HK sensitivity is 75% when specificity is set at 85%, and specificity is 70% when sensitivity is set at 90%.
  • For the ratio of 3-HK to TRP sensitivity is 80% when specificity is set at 82.5%, and specificity is 77.5% when sensitivity is set at 85%.

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EP09013088A 2005-04-06 2006-03-30 Marqueurs neuro-dégénératifs pour la maladie d'Alzheimer Not-in-force EP2146209B1 (fr)

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Application Number Priority Date Filing Date Title
PL09013088T PL2146209T3 (pl) 2005-04-06 2006-03-30 Neurodegeneratywne markery choroby Alzheimera
EP09013088A EP2146209B1 (fr) 2005-04-06 2006-03-30 Marqueurs neuro-dégénératifs pour la maladie d'Alzheimer

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EP05007558 2005-04-06
EP09013088A EP2146209B1 (fr) 2005-04-06 2006-03-30 Marqueurs neuro-dégénératifs pour la maladie d'Alzheimer
EP06723873A EP1866650B1 (fr) 2005-04-06 2006-03-30 Marqueurs neurodégénératifs pour dépression.

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EP2053405A4 (fr) * 2006-08-04 2009-11-11 Ajinomoto Kk Procédé d'évaluation de stress, appareil d'évaluation de stress, système d'évaluation de stress, programme d'évaluation de stress et support d'enregistrement associé
AT9843U1 (de) * 2007-03-27 2008-04-15 Kepplinger Berthold Dr Messung von biologischen markern
KR20220008944A (ko) 2008-01-18 2022-01-21 프레지던트 앤드 펠로우즈 오브 하바드 칼리지 체액 내에서 질병 또는 병태의 시그너쳐의 검출 방법
WO2009096502A1 (fr) * 2008-01-31 2009-08-06 Japan As Represented By President Of National Center Of Neurology And Psychiatry Marqueur pour la dépression et un état déprimé et détection et diagnostic l'utilisant
WO2009100243A2 (fr) * 2008-02-05 2009-08-13 University Of Miami Elavl4 en tant que prédicteur d’une dépression chez des patients atteints de la maladie d'alzheimer et de la maladie de parkinson
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DK1866650T3 (da) 2010-09-06
EP1866650B1 (fr) 2010-05-19
CY1110116T1 (el) 2015-01-14
EP1866650A1 (fr) 2007-12-19
HK1137219A1 (en) 2010-07-23
ATE468537T1 (de) 2010-06-15
JP2008537111A (ja) 2008-09-11
WO2006105907A1 (fr) 2006-10-12
NO20120452L (no) 2007-11-06
US20120196300A1 (en) 2012-08-02
ES2377704T3 (es) 2012-03-30
PL1866650T3 (pl) 2011-04-29
PT1866650E (pt) 2010-06-01
DE602006014379D1 (de) 2010-07-01
NO20075671L (no) 2007-11-06
ES2346467T3 (es) 2010-10-15
SI1866650T1 (sl) 2010-12-31
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DK2146209T3 (da) 2012-02-13
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